Method of potentiating drugs affecting the central nervous system and compositions therefor



2,807,566 METHOD OF POTENTIATING DRUGS AFFEfiT-ING THE CENTRALNERVOUS SYSTEM AND COM- POSITIONS THEREFOR Edwin J. Fellows, North Hills, Pa., assignor to Smith,

Kline, & French' Laboratories, Philadelphia, Pa., a corporation of Pennsylvania No Drawing. Application October 30, 1 153, Serial No. 389,499

2 Claims. Cl. 167-52) This invention relates to a new composition affecting the central nervous system and method of potentiating drugs affecting the central nervous system.

The composition inaccordance with this invention has been found to-be'of great efi'icacy in treating, for example, conditions requiring sedative, hypnosis and/or anti-convulsant action and which have heretofore been treated with barbiturates which are sedative-hynotics and/or anticonvulsants, paraldehyde, choral hydrate, 2-monobromisovalerylurea, allyisopropylacetyl-carbamide and bromdiethylacetylurea.

The composition according to this invention comprises the combination of a centrally acting drug, that is, a

drug having an affect on the central nervous system, and a compound which potentiates said drug.

More specifically, the drug used in the composition of this invention and which affects the'central nervous system is a sedative-hypnotic and/or anti-convulsant barbiturate, paraldehyde, chloral hydrate, 2-monobromisovalerylurea, allylisopropylace'tylcarbamide or brorndiethylacetylurea.

The following are exemplary of the barbiturates:

5-phenyl-5-ethylbarbituric acid (Phenobarbital) 5-isoamyl-S-ethylbarbituric acid (Amobar'bital) 5-ethyl-5-( l-methylbutylybarbituric acid (Pentobarbital) N-methyl-S-cyclohexenyLS-methyl barbituric acid (Evip 5-allyl-'5-(l-methylbutyl) barbituric acid (Seconal) N-methyl-5-ethyl-S-phenylbarbituric acid (Mebaral) S-N-butyl-S-ethyl barbituric acid (Butethal) and alkali metal salts of these compounds. Where a salt is used the sodium salt is preferred.

Although the above barbiturates are preferred and are particularly advantageous with this. invention, it will be appreciated that other barbiturates can be used equivalently.

The potentiating compound which is utilized in the composition in accordance with this inventionis an aminoalkyl ester of a diphenyl' acetic acid derivative or an acid addition salt thereof, the ester having the following structural formula:

where X=alkyl having not in excess of 8 carbon atoms or alkenyl having not in .excess of '8 carbon atoms; R: alkylene having from 2 to 8 carbon atoms; Y=a nitrogenlinked radical selected from v the group consisting of piperidino, NH2, NHR1, NR1R2, where R1 and R2 are selected from the group consisting of alkyl not in excess of, 8 carbon atoms, cycloalkylradicals not in excess of 8 carbon atoms, phenyl radicals and phenylalkyl radicals, the alkyl portion of the phenylalkyl not exceeding 8 carbon atoms.

The ester potentiates the central nervous effect of these drugs as evidenced, for example, by increasing the duration of their eifect.

Due to the markedly superior potentiation which re- 2,807,563 Patented Sept. 24, 1957 ice sults through its use, a potentiating compound within the scope of the following formula is preferred:

( uHE)2- -(|3OORY 1-diethylamino-2-ethyl-3-propyl 2,2-diphenylA-pentenoate 1 diethylarnino 2-ethyl-3-propyl 2,2-diphenyl-4-pentenoate hydrochloride 1-diethylamino-6-hexy 2,2-diphenyl-4-pentenoate l-diethylamino-G-hexyl 2,2-diphenyl-4-pentenoate hydrochloride l-diethylamino-S-pentyl 2,2-diphenyl-4-pentenoate hydrochloride I 1-diethylamino-4-butyl 2,2-diphenyl-4-pentenoate hydrobromide l-diethylamino-Spentyl 2,2-diphenyl-4-pentenoate sulfate l-diethylamino-G-hexyl 2,2-dipl'1enyl-4-pentenoate tar-trate B-Dihexylaminoethyl 2,2-dip'henyl pentanoate ,B-Diethylaminoethyl 2,2-diphenyl-4-pentenoate fl-Diethylarninoethyl 2,2-diphenyl-4-pentenoate hydrochloride fi-Diethylaminoethyl' 2,2-diphenyl-4-pentenoate hydrobromide fl-Diethylaminoethyl 2,2-diphenyl-4-pentenoate sulfate fi-Dimethylaminoethyl 2,2-diphenyl-4-pentenoate fl-Dimethylaminoethyl 2,2-diphenyl-4-pentenoate tartrate fl-Diinethylarninoethyl 2,2-diphenyl-4-pentenoate hydrobrornide fl-Dimethylaminoethyl 2,2-diphenyl-4-pentenoate benzoate fl-Dimethylaminoethyl 2,2-diphenyl-4-methyl-4-pentenoate ,B-Dimethyla-minoethyl'2,2-diphenyl-4-methyl-4-pentenoate hydrochloride ,B-Dimethylaminoethyl 2,2-diphenyl-4-methyl-4-pentenoate hydrobromide B-Dimethylaminoethyl 2,2-diphenyl-4-methyl-4-pentenoate citrate .p-Piperidinoethyl 2,2-diphenyl-4-pentenoate p-Piperidinoethyl 2,2-diphenyl-4-pentenoate hydrochloride [3-Piperidinoethyl 2,2-diphenyl-4-pentenoate hydrobromide fl-Piperidinoethyl 2,2-diphenyl-4-pentenoate sulfate p-Piperidinoethyl 2,2-diphenylpentanoate B-Piperidinoethyl 2,2-diphenylpentanoate hydrochloride ,B-Piperidinoethyl 2,2-diphenylpentanoate acetate fl-Piperidinoethyl 2,2-diphenylpentanoate sulfate fl-Diethylaminoethyl 2,2-diphenyl-4-methylpentanoate fi-Diethylaminoethy-l 2,Z-diphenyll-methylpentanoate hydrochloride fl-Diethylaminoethyl 2,2-diphenyl-4-methylpentanoate hydrobromide p-Diethylaminoethyl 2,2 diphenyl 4 methylpentanoate phosphate fi-Dimethylaminoethyl 2,2-diphenylpentanoate fl-Dimethylaminoethyl 2,2-diphenylpentanoate hydrochloride ,B-Dimethylaminoethyl 2,2-diphenylpentanoate hydrobromide fl-Dimethylamino'ethyl 2,2-diphenylpentanoate acetate fl-Diethylaminoethyl 2,2-diphenylpentanoate n'de p-Diethylaminoethyl 2,2-diphenylpentanoate hydrobromide fl-Diet-hylaminoethyl 2,2-diphenylpentanoate sulfate ,s- (Phenylethylamino) propyl 2,2 diphenyl 3 methyl-4-pentenoate fl-Diethylaminoethyl 2,2-diphenylpentanoate citrate fl-Diet-hylamonoethyl 2,2-diphenylpentanoate benzoate f3 (Phenylethylamino) propyl 2,2 diphenyl 3 methyl-4-pentenoate hydrochloride B (Phenylethylamino) propyl 2,2 diphenyl 3 methyl-4-pentenoate tartrate t3 (Phenylethylamino) propyl 2,2 diphenyl 3 methyl-4-pentenoate benzoate 'y-Dibenzylaminopropyl 2,2-diphenyl-4-hexenoate -Dibenzylaminopropyl 2,2-diphenyl-4-hexenoate hydrochloride 'y-Dibenzylaminopropyl 2,2-diphenyl-4-hexenoate acetate 'y-Dibenzylaminopropyl 2,2-diphenyl-4-hexenoate sulfate fi-Aminoethyl 2,2'diphenylhexanoate fl-Aminoethyl 2,2-diphenylhexanoate hydrochloride B-Aminoethyl 2,2-diphenylhexanoate hydrobromide fl-Aminoethyl 2,2-diphenylhexanoate sulfate fl-Benzylmethylaminoethyl 2,2-diphenylpentanoate fl-Benzylmethylaminoethyl 2,2-diphenylpentanoate hydrochloride ;8-Benzylmethylaminoethyl 2,2-diphenylpentanoate hydrobromide fl-Benzylmethylaminoethyl 2,2-diphenylpentanoate benzoate fl-Methylaminoethyl 2,2-diphenylpentanoate ,B-Methylaminoethyl 2,2 diphenylpentanoate hydrochlor de ,B-Methylaminoethyl 2,2-diphenylpentanoate hydrobromide B-Methylaminoethyl 2,2-diphenylpentanoate sulfate fl-Diethylaminoethyl 2,2-diphenyl-4-methyl-4-pentenoate fl-Diethylaminoethyl 2,2-diphenyl-4-methyl-4pentenoate hydrochloride ,B-Diethylaminoethyl 2,2-diphenyl-4-methyl-4-pentenoate tartrate p-Diethylaminoethyl sulfate B-(Cyclopentylethylamino)-ethyl 2,2-diphenylpentanoate 2,2-diphenyl-4-methyl-4-pentenoate p-(Cyclopentylethylamino) ethyl 2,2 diphenylpentanoate hydrochloride [3- (Cyclopentylethylamino -ethyl 2,2-dipheny1pentanoate hydrobromide fl(Cyclopentylethylamino)-ethyl 2,2-diphenylpentanoate citrate fi-(Cyclohexylethylamino) -ethyl 2,2-diphenylpentanoate 8-(Cyclohexylethylamino)-ethyl 2,2-diphenylpentanoate hydrochloride p-(Cyclohexylethylamino)-ethyl 2,2-diphenylpentanoate hydrobromide fi-(Cyclohexylethylamino)-ethyl 2,2-diphenylpentanoate sulfate fi-Dibenzylaminoethyl 2,2-diphenylhexanoate fl-Dibenzylaminoethyl 2,2-diphenylhexanoate hydrochloride fl-Dibenzylaminoethyl 2,2 diphenylhexanoate hydrobromide fi-Dibenzylaminoethyl 2,2-dipheuylhexanoate sulfate Aminoalkyl esters of diphenyl acetic acid having the above structural formula and the acid addition salts thereof are well known to the art and several methods suitable for their preparation are known. Thus, for example, reference may be had to the following:

1. Craig, Witt, Ullyot, Abstracts of the 116th Meeting of the American Chemical Society, September 123-23 (1949), page 4L. Smith, Kline & FrenchLaboratories.

2. Craig, Witt, Macko, Dacanay, Fellows and Ullyot, J. A. C. S. 73, 1939 (1951), March-Smith, Kline 85 French Laboratories.

3. Larsen, Ruddy, Elpern, McMullin, I. A. C. S. 71, 532 (1949), Feb1uarySterling Winthrop Research Institute.

The essential ingredients of the composition according to this invention will preferably be intimately admixed and may be included in widely varying proportions. It has been found that maximum potentiation occurs when the potentiating compound acts first. Thus, the composition of this invention is used to excellent advantage in multiple doses and in timed delay tablets, and the like.

Generally speaking, the selected potentiating ester will be used in an amount of from about 7 mgm./kgm. of body weight to about 20 mgmJkgm. of body weight. It is, however, preferred to use the selected potentiating ester in an amount of from about 3 mgm./kgm. of body weight to about 10 mgm./kgm. of body weight. The amount of potentiating ester will, of course, vary widely depending upon the centrally acting drug selected and the amount of potentiation desired.

Expressed in absolute amounts a satisfactory range of the potentiating ester is from 60 mg. to 1200 mg. and a preferred range is from 180 mg. to 600 mg.

The amount of the selected centrally acting drug to be potentiated will vary widely depending on the physiological effect to be achieved. Generally speaking, it is desir able to have from about the standard effective therapeutic dose (U. S. P.) of the selected drug to about one-fourth of the standard dose. It is preferred to use an amount in the range of from the standard efiective therapeutic dose to one-half of the standard dose. The standard effective therapeutic doses for the centrally acting drugs used in the composition of this invention are well known in the art.

The method in accordance with this invention comprises the administration internally of the essential ingredients of the above composition for concurrent physiological action. It is preferred to administer the potentiating ester first for maximum potentiation. The administration may be, for example, oral or by intravenous injection; and, if desired, the essential ingredients may be administered in a diiferent manner, i. e., one orally and one intravenously. The ranges given above for the essential ingredients are applicable to the method whether these ingredients are administered together or separately.

For administration the composition may be made up in various forms, as, for example, in a tablet, in a capsule, a powder, or a liquid, such as water, for oral administration. The essential ingredients may be extended with any desired excipient as, forexample, sugar of milk or starch. When prepared for injection, the essential ingredients may be mixed with any suitable vehicle, such as, for example, water, a polyhydric alcohol or a mixture thereof.

A highly efiicient preparation for oral use in accordance with this invention and based on an average body weight of about lbs. may be made up on any of the following formulae, it being appreciated that numerous other combinations and varying amounts of the individual ingredients can be utilized.

Example 1 Grams Chloral hydrate 0.6 p-Diethylaminoethyl 2,2-diphenylpentanoatc 0.5 Example 2 Paraldehyde 3.0 ,B-Diethylaminoethyl 2,2-diphenylpentanoate 0.5 Example 3 S-phenyl-S-ethylbarbituric acid 0.15 [3-Diethylaminoethyl 2,2-diphenylpentanoate 0.5 Example 4 S-isoamyl-S-ethylbarbituric acid 0.2 fl-Diethylaminoethyl 2,2-diphenylpentanoate 0.5 Example 5 Sodium 5-ethyl-5-( l-methylbutyl) barbiturate 0.1 fl-Diethylaminoethyl 2,2-diphenylpentanoate 0.5 Example 6 N-methyhS-cyclohexenyhS-methylbarbituric acid 0.25 ,e-Diethylaminoethyl 2,2-diphenylpentanoate 0.5

Example 43 Grams Chloral hydrate 0.6 fl-Diethylaminoethyl 2,2-diphenylpentanoate hydrochloride 0.5

Example 44 Paraldehyde 3.0 p-Diethylaminoethyl 2,2-diphenylpentanoate hydrochloride 0.5

Example 45 S-phenyl-S-ethylbarbituric acid 0.15 fi-Diethylaminoethyl 2,2-diphenylpentanoate Example 46 5-isoamyl-5-ethylbarbituric acid 0.2 fl-Diethylaminoethyl 2,2-diphenylpentanoate hydrobromide 0.5

Example 47 Sodium 5-ethyl-5'( l-methylbutyl)-barbiturate 0.1

B-Diethylaminoethyl 2,2-dipheny1pentanoate citrate 0.5 Example 48 N-methyl-5-cyclohexenyl-S-methylbarbituric acid 0.25 fi-Diethylaminoethyl 2,2-diphenylpentanoate citrate 0.5 Example 49 Sodium 5-allyl-5-( l-methylbutyl -barbiturate 0.1 fl-Diethylaminoethyl 2,2-diphenylpentanoate acetate 0.5 Example 50 N-methyl-S-ethyl-5phenylbarbituric acid 0.1

p-Diethylaminoethyl 2,2-diphenylpentanoate succinate 0.5

Example 51 2-monobromisovalerylurea 0.75 p-Diethylaminoethyl 2,2-dipheny1pentanoate hydrochloride 0.5

Example 52 Bromdiethylacetylurea 0.9 fl-Diethylaminoethyl 2,2-diphenylpentanoate tartrate 0.5

Example 53 Allylisopropylacetylcarbamide 0.375 fi-Diethylaminoethyl 2,'2-diphenylpentanoate benzeate .5

Example 54 N-methyl-S-cyclohexenyl--methy1barbituric acid (,5 p-Dimethylaminoethyl 2,2-diphenyl-4-pentenoate sulfate 0.

Example 55 5-phenyl-5'ethylharbituric acid 0.15

fl-Dimethylaminoethyl 2,2-diphenyl-4-pentenoate phosphate 0.;

Example 56 Chloral hydrate 0.6 fl-Diethylaminoethyl 2,2-diphcnyl-4-pentenoate hydrochloride -5 Example 57 Paraldehyde 3.0 p-Diethylaminoethyl 2,2-dipheny1-4-pentenoate hydrochloride 0.5

Example 58 S-phenyl-S-ethylbarbituric acid 0.15 fi-Dimethylaminoethyl 2,2-diphenyl-4-methyl-4- pentenoate tartrate 0.5

8 Example 59 Grams 5-isoamyl-S-ethylbarbituric acid 0.2

p-Piperidinoethyl 2,2-diphenyl-4-pentenoate hydrobromide r 0.5 I 0 Example 60 Sodium 5-ethy1-5-( l-methylbutyl) -barbiturate 0.1 fl-Piperidinoethyl 2,2-diphenylpentanoate citrate..- 0.5 Example 61 N-methyl-S-cyclohexenyl-S-methylbarbituric acid 0.25 B-Diethylaminoethyl 2,2-dipl1eny1-4-methy1-pentanoate citrate 0.5

Example 62 Sodium 5-allyl-5-(l-methylbutyl)-barbiturate 0.1 fl-Dimethylaminoethyl 2,2-diphenylpentanoate acetate 0.5

Example 63 N-methyI'S-ethy1-5-phenylbarbituric acid 0.1 fl-(Phenylethylamino)-propyl 2,2-dipheny1-3-methy1-4-pentenoate succinate 0.6

Example 64 2-monobromisovalerylurea -a 0.75 -Dibenzylarninopropyl 2,2-diphenyl-4-hexenoate hydrochloride 0.6

Example 65 Bromdiethylacetylurea 0.9 B-Aminoethyl 2,2-diphenylhexanoate tartrate 0.4 Example 66 Allylisopropylacetylcarbamide 0.375 B-Benzy1methylaminoethy1 2,2-diphenylpentanoate benzoate 0.5

Example 67 Sodium 5-phenyl-5-ethylharbiturate 0.15 p-Diethylaminoethyl 2,2-dipheny1pentanoate hydrochloride 0.5

Example 68 Sodium.5-isoamyl-S-ethylbarbiturate 0.2 B-Diethy1aminoethyl 2,2-diphenylpentanoate hydrochloride 0.5

Example 69 5-ethyl-5-(l-methylbutyD-barbituric acid 0.1 fl-Diethylarninoethyl 2,2-diphenylpentanoate hydrochloride Example 70 Sodium N methyl-5-cyclohexenyl-5-mcthylbarbiturate 0.25 ,BDiethylaminoethyl 2,2-diphenylpentanoate hydrochloride 0.5

Example 71 5-allyl-5-(l-methylbutyD-barbituric acid 0.1 fl-Diethylaminoethyl .2,2-diphenylpentanoate hydrochloride 0.5

Example 72 Sodium N-methyl-S-ethyl-S-phenylbarbiturate- 0.1 B-Diethylaminoethyl 2,2-diphenylpentanoate hydrochloride 0.5

Example 73 S-N-butyl-S-ethylbarbituric acid 0.1. [3-Diethylaminoethyl 2,2-diphenylpentanoate hy drochloride 0.5

It is not desired to be limited except as 'set forth in the following claims, it being understood that the above examples are merely illustrative.

This application is a continuation-in-part of application Serial No. 310,141, filed September 17, 1952, now abandoned.

What is claimed is:

1. A medicinal preparation comprising a centrally acting drug selected from the group consisting of barbiturates, Z-monobromisovaierylurea, allylisopropylacetyl carbamide and bromdiethylacetylurea and a component to substantially increase the effectiveness of the centrally acting drug, said component being selected from the group consisting of an ester of a diphenylacetic acid derivative and organic and inorganic acid addition salts of said ester, the ester having the following structural formula:

wherein X is selected from a group consisting of alkyl having not in excess of 4 carbon atoms and 'alkenyl having from 3 to 4 carbon atoms, R is alkylene having from 2 to 4 carbon atoms and Y is a nitrogen-linked radical selected from the group consisting of piperidino, primary amino, secondary alkyl amino having not in excess of 4 carbon atoms, di-alkyl amino with each alkyl group having not in excess of 4 carbon atoms, secondary cycloalkyl amino having from 5 to 6 carbon atoms, di-cycloalkyl amino having from 5 to 6 carbon atoms in each cycloalkyl group, secondary benzylamino, dibenzylamino, secondary phenethylamino and diphenethylamino.

2. The method of potentiating the sedative-hypnotic effect of a centrally acting drug selected from the group consisting of a barbiturate, 2-monobromisovalerylurea, allylisopropylacetylcarb'amide and bromdiethylacetylurea,

10 which comprises administering internally for concurrent physiological action with said drug a member selected from the group consisting of an ester of a diphenylacetic acid derivative and organic and inorganic acid addition salts of said ester, the ester having the following structural formula:

wherein X is selected from the group consisting of alkyl having not in excess of 4 carbon atoms and alkenyl having from 3 to 4 carbon atoms, R is alkylene having from 2 to 4 carbon atoms and Y is a nitrogen-linked radical selected from the group consisting of piperidino, primary amino, secondary alkyl amino having not in excess of 4 carbon atoms, di-alkyl amino with each alkyl group having not in excess of 4 carbon atoms, secondary cycloalkyl amino having from 5 to 6 carbon atoms, di-cycloalkyl amino having from 5 to 6 carbon atoms in each cycloalkyl group, secondary benzylamino, dibenzylamino, secondary phenethylamino and diphenethylamino.

References Cited in the file of this patent Ludwig: Rep'ertorium Pharmazeutischer Spezialpraparate (2. unveranderte Auflage), p. 957.

Larsen: 1. of the Am. Chem. Soc., vol. 71 (1949), pp. 532, 533.

Craig: I. of the Am. Chem. Soc., vol. 73 (1951), pp. 1339-1441.

Tobolowsky: J. Lab. Clin. Med., vol. 28 (Oct. 1942.), pp. 3138.

Gilman: J. PharmacoL, vol. 74' (Mar. 1942), pp. 290*- 308. 

1. A MEDICINAL PREPARATION COMPRISING A CENTRALLY ACTING DRUG SELECTED FROM THE GROUP CONSISTING OF BARBITURATES, 2-MONOBROMISOVALERYLUREA, ALLYLISOPROPYLACETYLCARBAMIDE AND BROMDIETHYLACETYLUREA AND A COMPONENT TO SUBSTANTIALLY INCREASE THE EFFECTIVENESS OF THE CENTRALLY ACTING DRUG, SAID COMPONENT BEING SELECTED FROM THE GROUP CONSISTING OF AN ESTER OF A DIPHENYLACETIC ACID DERIVATIVE AND ORGANIC AND INORGANIC ACID ADDITION SALT OF SAID ESTER, THE ESTER HAVING THE FOLLOWING STRUCTURAL FORMULA: 